Copper Catalyzed Fluorination of Aryl Halides

项目摘要。 芳基氟基序在一系列重要化合物中普遍存在。>25%的农用化学品， >20%的药物含有氟，通常以芳基氟的形式存在。18F是最受欢迎的 正电子发射断层扫描（PET）中的放射性同位素，PET是一种用于诊断和 治疗阿尔茨海默氏症和帕金森氏症等疾病。尽管芳基氟化物在工业中的广泛使用， 在这些领域，目前很少有用于其合成的稳健的和官能团耐受的方法。 因此，开发更有效的方法将氟引入有机分子是一个优先事项。一 有前途的方法是由容易获得的芳基卤化物过渡金属催化合成芳基氟化物。 然而，很少有报道的系统，这种转变。两种现有的基于Cu的系统使用简单的 Cu盐和造成需要解决的显著缺点，例如需要高的pH值。 温度，过量的昂贵的氟化物源（AgF），超化学计量的Cu，或对特定的限制， 指导组。因此，开发克服这些限制的系统是极其重要的 外地未解决的问题。为了改进这些系统，我们的目标是解决关键挑战 Cu固有的：（i）大多数CuIF络合物对反硝化形成无活性的Cu 0和CuF 2不稳定 和（ii）氧化加成步骤的困难。为了克服这些问题，我们将从简单的铜盐 至由N-杂环卡宾（NHC）、环烷基氨基卡宾（Cyclic alkyl amino carbene） （CAAC）或相关配体。我们假设这些配体将稳定CuI中间体，以及有利于 氧化加成，导致更有效的催化剂。具体来说，我们的目标是使用卡宾支撑的Cu 配合物：（1）研究配体性质对卤代芳烃化学计量比的影响，（2）开发 一系列药物相关芳基卤化物支架的催化降解（3）合成18F标记的 用于PET成像的示踪剂分子。这些目标的完成将导致改进系统， 芳基卤化物的合成，可应用于药物、农用化学品和PET示踪剂的合成。 已取得初步结果，支持每个拟议目标的可行性。

Project Summary. The aryl fluoride motif is prevalent in a range of important compounds. >25% of agrochemicals and >20% of pharmaceuticals contain fluorine, often in the form of aryl fluoride. Additionally, 18F is the favored radioisotope in Positron Emission Tomography (PET), an in-vivo imaging technique used in the diagnosis and treatment of diseases such as Alzheimer's and Parkinson's. Despite the widespread use of aryl fluorides in these areas, there are currently very few robust and functional group tolerant methods for their synthesis. Developing more efficient methods to introduce fluorine into organic molecules is therefore a priority. One promising method is the transition metal catalyzed synthesis of aryl fluorides from readily available aryl halides. However, there are few reported systems for this transformation. The two prior Cu-based systems use simple Cu salts and pose significant drawbacks that need to be addressed, such as the requirement for high temperatures, an excess of expensive fluoride source (AgF), supersoichiometric Cu, or limitation to specific directing groups. Developing systems that overcome these limitations is therefore an extremely important unsolved problem in the field. In order to improve on these systems, we aim to address key challenges inherent to Cu: (i) the instability of most CuIF complexes to disproportionation to form inactive Cu0 and CuF2 and (ii) the difficulty of the oxidative addition step. To overcome these issues we will move from simple Cu salts to well-defined copper complexes supported by N-heterocyclic carbenes (NHCs), cyclic alkyl amino carbene (CAACs), or related ligands. We hypothesize that these ligands will stabilize CuI intermediates, as well as favor oxidative addition, leading to more efficient catalysts. Specifically, we aim to use carbene-supported Cu complexes to: (1) study the effects of ligand properties on stoichiometric fluorination of aryl halides, (2) develop catalytic fluorination of a range of pharmaceutically relevant aryl halide scaffolds (3) synthesize 18F labeled tracer molecules for use in PET imaging. Completion of these aims will result in improved systems for the fluorination of aryl halides that can be applied to synthesis of pharmaceuticals, agrochemicals and PET tracers. Preliminary results have been obtained that support the feasibility of each proposed aim.